Fragile X syndrome (FXS) carriers have FMR1 alleles, called premutations, with an intermediate number of 5'-untranslated CGG-repeats between patients (>200 repeats) and normal individuals (<60 repeats). Fragile X-associated tremor/ataxia syndrome (FXTAS), a late age of onset neurodegenerative disorder, has been recognized in older males of fragile X premutation carriers, which is uncoupled from the neurodevelopmental disorder, FXS. Several lines of evidence, including ours, have led to the proposal of an RNA-mediated gain-of-function toxicity model for FXTAS, in which rCGG repeat-binding proteins (RBPs) could become functionally limited by their sequestration to lengthy rCGG repeats. Through small molecule screen, we have identified potent small molecules that could suppress rCGG-mediated neurodegeneration in FXTAS Drosophila model. In this translational R21 proposal, we plan to further test these compounds in FXTAS mouse model and identify additional small molecules that could suppress rCGG- mediated neuronal toxicity. PUBLIC HEALTH RELEVANCE: Fragile X-associated tremor/ataxia syndrome (FXTAS), a late age of onset neurodegenerative disorder, is mainly associated with older males of fragile X premutation carriers. We have identified small molecules that could suppress rCGG- mediated neurodegeneration using FXTAS Drosophila model. In this translational R21 application, we plan to further validate these compounds in FXTAS mouse model, which could provide potential therapeutic interventions for FXTAS.